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 »  Introduction
 »  Case report
 »  Material and methods
 »  Results
 »  Discussion
 »  References

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Year : 2000  |  Volume : 48  |  Issue : 2  |  Page : 174-7

Molecular basis of cholesterol feedback lesion in CNS tumours.

Department of Experimental Medicine, Biotechnology and Neurosurgery, Postgraduate Institute of Medical Education and Research, Chandigarh, 160012, India.

Correspondence Address:
Department of Experimental Medicine, Biotechnology and Neurosurgery, Postgraduate Institute of Medical Education and Research, Chandigarh, 160012, India.

  »  Abstract

An important feature of malignant transformation of tumours is the loss of cholesterol feedback inhibition mechanism (cholesterol-feedback lesion) that regulates mevalonate pathway recognized to play a crucial role in cellular growth, death and differentiation. Recently, it was shown that Receptor-C(k)-dependent signalling regulates genes involved in maintaining cellular cholesterol homeostasis through a transcription factor sterol response element binding protein (SREBP) having affinity for sterol regulatory element (SRE) present in the promoter region of these genes. The present study revealed that CNS tumours exhibit overexpression of Receptor-C(k) gene product which was accompanied by their inability to express SREBP gene product and this phenomenon has the inherent capacity to initiate the cholesterol feedback lesion in these tumours. Based upon these and our earlier studies, we propose for the first time that this loss of cholesterol feedback control may be responsible for the initiation of these tumours.

How to cite this article:
Kaul D, Khosla V K. Molecular basis of cholesterol feedback lesion in CNS tumours. Neurol India 2000;48:174

How to cite this URL:
Kaul D, Khosla V K. Molecular basis of cholesterol feedback lesion in CNS tumours. Neurol India [serial online] 2000 [cited 2021 Sep 28];48:174. Available from:

[TAG:2]Introduction [/TAG:2]
Incontrovertible evidence now exists that cellular cholesterol homeostasis is maintained by the feedback mechanism involving cholesterol molecule itself as an end-product repressor of genes (coding for HMGCoA Synthase, HMGoA reductase and apo'B' - specific LDL receptor) through a transcription factor sterol response element binding protein sterol regulatory element binding protein (SREBP) having affinity for a conserved sterol regulatory sequence (SRE) present in the promoter region of these genes.[1],[2] The importance of this cholesterol feedback control to human health was established by the findings which revealed a direct correlation between loss of this end-product control of cellular cholesterol metabolism (cholesterol feedback lesion) and carcinogenesis.[3],[4],[5] The fact that cholesterol is a hydrophobic molecule, which resides exclusively in lipoproteins and cell membranes, raised two fundamental questions: a) How does the cell sense the level of cholesterol? and b) How is this sterol-dependent signalling transmitted to the nucleus for gene regulation? Recent studies, directed to resolve these questions, led to the discovery of a novel cell surface sterol-sensor (receptor) designated as 'Receptor-Ck' based upon its typical characteristics especially having high affinity for cholesterol (C) moiety in various types of lipoproteins as well as sterol-dependent intrinsic tyrosine kinase (K) activity.[6] This Receptor-Ck was not only shown to be ubiquitously present in various human organs (such as liver, aorta, adrenal cortex, brain etc.) but also was responsible for the initiation of cholesterol-dependent signalling pathway[6] [Figure.1] which, in turn, was shown to regulate genes involved in cellular cholesterol homeostasis.[7],[8] The selective and conspicuous absence of Receptor-Ck gene expression in human leukaemic cells as well as lymphocytes from untreated CML patients[6],[9] explained for the first time the molecular basis of cholesterol feedback lesion widely observed in these leukaemic cells.[6] It is, therefore, logical to predict from [Figure. 1] that cells, which are unable to express Receptor-Ck gene or 125kDa SREBP, must exhibit the phenomenon of 'cholesterol feedback lesion' leading to the process of carcinogenesis. Based upon these facts, the present investigation was undertaken to study the expression of genes coding for Receptor-Ck and SREBP in tumours of central nervous system.

   »   Material and methods Top

Specific antibody against SREBP was procured from Santa Cruz Biotechnology, U.S.A. Polyclonal
monospecific antibody against Receptor-Ck was raised in our laboratory.[9] All other reagents/chemicals used in the study were procured from Sigma.
Tumour tissues were taken from 24 patients operated for intracranial tumours in the neurosurgery department of Postgraduate Institute of Medical Science, Chandigarh. Out of these 24 cases, normal brain parenchyma was taken in 4 cases. These tissues were classified into various types of tumours on the basis of histopathological/clinical examination. The tissue samples were homogenised in 20mM tris-HCl buffer pH 7.4 containing 2mM EDTA+2mM EGTA + protease inhibitors. The homogenate was centrifuged at 20,000 rpm at 10oC. The amount of protein from each supernatant was quantified and subsequently loaded in equal amount to each well in the SDS-PAGE as well as ELISA plate. Using standard western blotting procedure and ELISA procedure, the expression of Receptor-Ck and SREBP was immuno detected in the protein extract of each tissue specimen as per the procedure reported earlier. High standards of ethics was employed in carrying out the investigation.

   »   Results Top

The results of the present investigation unambiguously revealed that: a) expression of Receptor-Ck is higher in glioblastomas as compared to adenomas and meningiomas [Figure.2b] expression of SREBP was either negligible or absent in all the types of tumours studied [Figure.2c] expression of Receptor-Ck was more in tumours as compared to normal brain
parenchyma adjacent to these tumors [Figure.3d] expression of SREBP as well as its cleaved active product (47kDa) was only observed in normal parenchyma adjacent to these tumours and was totally absent in tumours [Figure.4]. These results indicate that all types of tumours exhibit 'cholesterol feedback lesion' due to their inability to express SREBP gene product.

   »   Discussion Top

There is general recognition of the fact that cholesterol-dependent feedback control is of crucial importance in the regulation of DNA replication, cell growth and cell death.[3],[11] The consistency with which the loss of cholesterol feedback system occurs in malignant cells, coupled with the findings that this defect precedes under premalignant conditions, supports the hypothesis that deranged cholesterogenesis may be involved in the early stages of carcinogenesis.[3] Further, the farnesyl residues, derived from the conversion of mevalonate to cholesterol, also have an important regulatory role in cellular growth. Post-translation farnesylation of the ras proteins (which are involved in the regulation of cell replication) is required for the attachment to the cell membrane and is necessary for ras-mediated malignant transformation of cells.[5] A new dimension was added by the finding that leukaemic cells exhibit 'cholesterol feedback lesion' as a result of their inability to express Receptor-Ck gene. In the present study, although the brain tumours exhibit overexpression of Receptor-Ck, they lack the expression of 125kDa SREBP through which Receptor-Ck dependent signalling regulates the various genes involved in maintaining cholesterol homeostasis [Figure.1]. Receptor-Ck-dependent signalling has also been shown to regulate other genes coding for Bcl-2 (repressor of apoptosis), Cyclin 'D', C-fos, C-Myc which initiate DNA replication.[6],[12] Based upon these findings we propose that 'cholesterol feedback lesion' can arise in a cell due to its inability to express either Receptor-Ck or SREBP and this loss of cholesterol feedback system has the inherent capacity to transform the cell into a malignant state.

  »   References Top

1.Brown MS, Goldstein JL: The SREBP pathway: Regulation of cholesterol metabolism by proteolysis of a membranebound transcription factor. Cell 1997; 89: 331-340.   Back to cited text no. 1    
2.Stark HC, Weinberger O, Wenberger J: Common double and single stranded DNA binding factor for a sterol regulating element. Proc Natl Acad Sci USA 1992; 89: 2180-2184.   Back to cited text no. 2    
3.Siperstein MD: Role of cholesterogenesis and isoprenoid synthesis in DNA replication and cell growth. J Lipid Res 1984; 25: 1462-1468.   Back to cited text no. 3    
4.Polsky FI, Brown MS, Siperstein MD: Feedback control of cholesterol synthesis in circulating granulocytes and deletion of feedback control in granulocytic leukaemia. J Clin Invest 1973; 52: 65a.   Back to cited text no. 4    
5.Buchwald H: Cholesterol inhibition, cancer and chemotherapy. Lancet 1992; 339: 1154-1156.   Back to cited text no. 5    
6.Kaul D: Receptor-Ckand leukemogenesis. Leuk Res 1998; 22: 389-394.   Back to cited text no. 6    
7.Goel R, Singh J, Kaul D: Receptor-Ck-dependent signalling regulates LDL receptor gene transcription. Mol Cell Biochem 1997; 169: 79-83.   Back to cited text no. 7    
8.Kaul D, Singh J: Exogenous cholesterol initiated transmembrane signalling pathway regulates cholesterogenesis in human platelets. Cell Signal 1994; 6: 141-145.   Back to cited text no. 8    
9.Kaul D, Singh J: Does Receptor-Ck deficiency initiate leukaemia? Cancer Lett 1997; 112: 199-202.   Back to cited text no. 9    
10.Nicolas C, Ghodira I, Faure JP et al: Identification of arrestin-like proteins in human megakaryocytic cell (HEL cells). Platelets 1998; 9: 55-62.   Back to cited text no. 10    
11.Vaux DL, Strasser A: The molecular biology of apoptosis. Proc Natl Acad Sci USA 1996; 93: 2239-2244.   Back to cited text no. 11    
12.Kaur M, Kaul D, Sobti RC: Receptor-Ck-dependent regulation of genes involved in cell cycle. Mol Cell Biochem 1998; 187: 137-142.   Back to cited text no. 12    


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